tbuckley/cabot-search huggingface dataset:
Circulating tumor DNA-based molecular residual disease detection for the monitoring of high-grade serous ovarian cancer.
Authors: Xiang Ying, Xiaocui Zheng, Yizhi Wang, Jiarui Li, Xing Li, Guomin Lin, Kai Wang, Xipeng Wang
Journal: Journal of Clinical Oncology (2023)

e17600 Background: The current standard treatment of epithelial ovarian cancer includes surgery and platinum-based chemotherapy. Most of the patients are sensitive, but still over 70% of patients have recurrence or disease progression. Post-operative circulating tumor DNA (ctDNA)-based minimal residual disease (MRD) test can be a potential biomarker for monitoring the disease. Methods: Stage II-IV high-grade serous ovarian cancer (HGSOC) patients were recruited in this study. Tumor tissues were collected for whole exome sequencing (WES; 300x). Germline mutations were excluded by paired white blood cell test. Proprietary algorithm was used to select 30-40 single nucleotide variants (SNV) for each patient. Blood samples were collected at diagnosis, after surgery, after chemotherapy, and during adjuvant treatment, and MRD was detected by multiplex polymerase chain reaction (PCR)-based sequencing (100,000x) using the customized panel. Results: At the time of analysis, WES was performed in 20 patients, of which 11 of them harbored HRR pathway-related mutations, including 5 BRCA1, 4 BRCA2, 1 ATM, and 1 FANCL. 7 patients had completed MRD monitoring for 3 times (pre-surgery, post-surgery, and post-chemotherapy). 71.4% (5/7) of patients were positive for MRD at baseline, with a median variant allelic frequency (VAF) of 2.79%. The VAF at baseline was positively associated with CA125 level at baseline (Pearson R = 0.937，p = 0.002). 2 patients were positive for MRD after surgery (VAF = 0.09% and 0.04%). One of them presented with multiple diverse lesions and the CA125 level returned normal after surgery and 8 cycles of chemotherapy. Another patient had an abnormal CA125 level of 1597 U/ml after surgery. All the 7 patients were negative for MRD after completion of chemotherapy. Follow-up is ongoing. Conclusions: We preliminary proved the feasibility of dynamic monitoring with MRD in epithelial ovarian cancer patients. Over 70% of HGSOC patients were MRD-positive at baseline. The MRD status was generally consistent with the clinical status of the patients. The performance of MRD in predicting recurrence of HGSOC is still under investigation. Clinical trial information: NCT05027828 .
Examining the effect of dementia on hospitalization outcome for GI cancer: A nationwide retrospective analysis.
Authors: Chun-Wei Pan, Wei-Lin Pan, Bhanu Siva Mohan Pinnam Pinnam
Journal: Journal of Clinical Oncology (2023)

e16336 Background: Dementia is a debilitating condition affecting a significant fraction of the elderly, with far-reaching consequences. It is an active field of research, with current emphasis on modifiable risk factors as well as treatment. Considering the limitations that dementia imposes on the management of other medical conditions, we attempt to study its association with, and impact on hospitalizations for gastrointestinal (GI) cancers. Methods: We queried the National Inpatient Sample databases for the years 2016 through 2020, using International Classification of Diseases, tenth revision (ICD-10) codes to include all adult admissions with esophageal, gastric, colorectal, biliary Tract, liver, and pancreatic cancers. We further stratified this cohort based on the presence of a secondary diagnosis of dementia. STATA 17 was used to perform a multivariate regression analysis to compare outcomes in the two cohorts, while adjusting for potential confounders. Results: The study identified 280,180 patients with GI cancer, of whom 4.7% (13,135) had a secondary diagnosis of dementia. The cohort with dementia was found to have a higher proportion of females (47.0%) compared to the non-dementia cohort (40.8%) and a higher median age (77.9 years vs 66.9 years). Additionally, this cohort had a higher prevalence of other medical comorbidities, with 98.2% having a Charlson comorbidity index (CCI) greater than 3 compared to 87.8% in the non-dementia cohort. The primary outcome of the study was in-patient mortality, which was stratified by age groups. In the 41-65 years old group, the mortality rate was higher in the dementia cohort (16.3%) compared to the non-dementia cohort (8.6%), with an adjusted odds ratio (aOR) of 1.96 (95% CI: 1.10-3.48, P&lt;0.05). In the 65-75 years old subgroup, the mortality rate was also higher in the dementia cohort (13.1%) compared to the non-dementia cohort (8.6%), with an aOR of 1.48 (95%CI: 1.14-1.93, P&lt;0.05). In the above-75-year-old subgroup, the mortality was higher in the dementia cohort (11.7%) compared to the non-dementia cohort (8.5%) (aOR: 1.35; 95%CI: 1.16-1.58, P&lt;0.05). Conclusions: Hospitalizations with GI cancer, with a secondary diagnosis of dementia, have higher odds of in-patient mortality compared to those without dementia. This was observed across all age groups. The dementia cohort also had a higher proportion of females and a higher median age, along with a higher prevalence of multiple comorbidities. These findings suggest that individuals with gastrointestinal cancer and dementia face a higher risk of in-patient mortality, highlighting the importance of considering dementia as a part of care planning in patients with GI cancer. [Table: see text]
Efficacy and safety of anlotinib hydrochloride combined with nivolumab in the treatment of advanced upper gastrointestinal tumor as second-line or later-line therapy: The results of gastric cancer cohort.
Authors: Yuehong Cui, Yiyi Yu, Jing Wu, Qian Li, Li Liang, Yan Wang, Shan Yu, Tianshu Liu
Journal: Journal of Clinical Oncology (2023)

e16015 Background: The upper gastrointestinal tumors, such as gastric adenocarcinoma (GAC) and esophageal squamous cell carcinoma (ESCC), have high rates of incidence and poor prognosis in our country, lacking of efficient therapy after failure of first-line regimen. Despite available treatment, there are still huge unmet medical needs of second-line or later-line therapy for patients with GAC or ESCC. Therefore, we will investigate the efficacy and safety of Anlotinib Hydrochloride (a multi-target tyrosine kinase inhibitor) combined with Nivolumab (PD-1 antibody) in GAC and ESCC. Methods: Patients with unresectable or metastatic GAC or ESCC who have failed standard therapy were treated by Anlotinib Hydrochloride 12mg/day orally for two weeks and Nivolumab 360mg every 3 week until the disease progression or intolerable adverse effects occurring. The study protocol was registered on ClinicalTrial.gov (NCT04503967,07/08/2020). The primary endpoint of this study was ORR (Objective Response Rate). The secondary endpoints were PFS (Progression-Free Survival), OS (Overall Survival), DCR (Disease Control Rate), and safety. Results: Gastric adenocarcinoma cohort would be reported only. From December 2020 to September 2022, 45 patients were enrolled in gastric adenocarcinoma cohort. There were 34 male patients and 11 female patients. The median age was 59 years. The percentage of gastric cancer patients with second-line and later-line treatment were 62.2% and 37.8%, respectively. 2 patients (4.4%) achieved complete remission (CR), 11 patients (24.4%) got partial remission (PR), and 15 patients (33.3%) got stable disease (SD). The ORR (CR+PR) was 28.9%, and DCR (CR+PR+SD) was 62.2%. Among 28 patients (62.2%) treated as second-line therapy, ORR was 32.1%, and DCR was 57.0%. As for later-line therapy of 17 patients, ORR and DCR were 23.5% and 70.6%, respectively. The median follow-up duration was 15.0 months (95% CI 8.17~21.83), then median PFS was 3.80±0.94 months, and median OS was 11.10±3.04 months. When the patients were treated as second-line therapy, median PFS was 3.0±0.97 months, and median OS was 14.50±3.89 months. Median PFS and OS in later-line patients of gastric adenocarcinoma were 3.80±1.30 months and 8.0±0.68 months, respectively. 36 patients (80%) had treatment-related adverse events (TRAEs). More than 10% of incidence rate included hypothyroidism (n=8), liver dysfunction (n=6), and rash (n=6). G3-4 of TRAEs were hypothyroidism (n=1), liver dysfunction (n=1), palmar-plantar erythrodysesthesia (n=1), rash (n=1), and hypophysitis (n=1). Conclusions: Anlotinib hydrochloride combined with Nivolumab showed effective clinical response and tolerable safety in second-line or later-line treatment of advanced gastric adenocarcinoma. Clinical trial information: NCT04503967 .
Comprehension characterization of prostate cancer cell lines identified JAK-STAT3 signaling in lineage-switched non-neuroendocrine cells.
Authors: Siyuan Cheng, Lin Li, Xiuping Yu
Journal: Journal of Clinical Oncology (2023)

e17005 Background: Prostate cancer (PCa) is the most diagnosed cancer type among American men. Androgen receptor (AR) targeted therapy as the gold standard of PCa has been challenged by treatment resistance. Lineage plasticity enables PCa cells to transit from prostate luminal epithelia to alternative lineages to bypass their dependency on AR signaling. Previously we established prostatic HOX code to study the prostatic lineage. We found that cells with neuroendocrine (NE) phenotype have a lineage switch. Besides, a subgroup of AR negative, NE negative samples also display lineage switch, among which is DU145, a human PCa cell line. Methods: RNA-seq data of PCa cell lines were obtained from GEO then aligned and quantified using human GRCh38 genome with STAR-Salmon pipeline. Downstream differential expression and enrichment analysis was performed with R. Immunohistochemistry (IHC) was used to assess protein levels on cell line derived xenografts. Results: 45 RNA-seq datasets of 6 prostate adenocarcinoma cell lines (VCaP, LNCaP, C4-2, 22RV1, PC3 and DU145) and 8 RNA-seq datasets of neuroendocrine prostate cancer cell line (H660) passed quality control. Principle component analysis indicates that samples from the same cell line had similar transcriptomes. Differential expression analysis followed by gene function enrichments analysis identified the marker genes and key signaling pathways of each cell line. HOX code analysis confirmed previous conclusion that all PCa cell lines but DU145 and H660 samples maintained prostatic HOX code. IHC staining on cell line-derived xenografts confirmed the protein expression of selected marker genes (TUBB2B for H660, HGF for VCaP and 22RV1, CXCL1 and KRT7 for DU145 and PC3). The three AR-negative PCa cell lines were further characterized in terms of AR/ NE activity scores, transcriptome identities, HOX codes. These analyses demonstrated that PC3 is a prostate progenitor like cell line, H660 is a lineage-switched NE cell line, and DU145 is a lineage-switched non-NE cell line. Further, signaling enrichment analysis revealed that DU145 cells had higher JAK-STAT3 signaling activity compared to other cell lines. IHC staining detected strong p-STAT3 signals on DU145-derived tumors but not on any other cell line-derived tumors. Conclusions: Human PCa cell lines were fully characterized based on their transcriptomes with high sample numbers. PC3 represents cells dedifferentiated into progenitor stage. DU145 and H660 represent cells that further trans-differentiate into alternative lineages. Neuron master regulators drive H660 cells into NE lineage and STAT3 drives DU145 cells into a non-NE lineage. DU145, representing a non-NE PCa class that have lost prostatic lineage, would be a suitable model system to study JAK-STAT targeting therapy.
AX-0085, a novel AXL kinase inhibitor, and effects on osimertinib-resistance in non–small-cell lung cancer.
Authors: Myeong Jun Choi, Byung-Ho Rhie, SangHyeon Woo, Si-Eun Yun, Young Jun Park, Jaesang Kim, Ramakrishna Suresh, Kye-Seong Kim
Journal: Journal of Clinical Oncology (2023)

e15121 Background: Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) having high efficacy in treating patients with advanced non-small cell lung cancer (NSCLC) with EGFR activating mutations and EGFR T70M mutations. Although, osimertinib is a frontline anticancer agent for treating NSCLC, many patients inevitably develop osimertinib-resistance tumor recurrence. The activation of AXL was reported to be a major factor driving osimertinib-resistance in NSCLC. Thus, AXL is a promising therapeutic target for the treatment of osimertinib-resistant NSCLC, and we developed a new small-molecule AXL inhibitor, AX-0085. Methods: We established osimertinib-resistant cell lines from EGFR-mutated NSCLC cell lines, HCC827 and H1975, after high dose exposure and stepwise exposure to osimertinib in culture. We investigated the cell viability of AX-0085 and other kinase inhibitors, and the anti-tumor activity of AX-0085 on the proliferation, migration, apoptosis, and epithelial-mesenchymal transition (EMT) in osimertinib-resistant cells. Results: Compared to the parental cells, IC 50 of resistant cell to osimertinib was significantly increased and osimertinib-resistant cells showed remarkably increased expression of AXL/pAXL and p-SRC as compared to the parental HCC827 cell. AX-0085 was completely blocked the AXL and SRC activation but EGFR inhibitors (gefitinib and osimertinib) did not inhibit the activation of AXL and SRC in the osimertinib-resistant cell line. AX-0085 (IC 50 : 4.4nM for AXL kinase in cell-based kinase assay) was one of the most potent AXL inhibitors and showed the strongest cytotoxicity against osimertinib-resistant cells compared to other kinase inhibitors. AX-0085 effectively down-regulated mRNA level of AXL and AXL regulating transcription factors in NSCLC cell lines such as HCC827 and H1975. AX-0085 treatment effectively inhibited the activation of AXL in acquired osimertinib-resistant cells and decreased the mRNA level of AXL and AXL regulating transcription factors. AX-0085 significantly inhibited the cell proliferation, apoptosis, migration, and EMT in acquired osimertinib-resistant cells. Conclusions: Our results showed that AX-0085 selectively inhibits the activation of AXL to overcome acquired resistance to osimertinib, suggesting an effective AXL-based therapy for patients with osimertinib-resistant tumors. Currently, AX-0085 is undergoing non-clinical trials.
Mobile-based multimodal rehabilitation including exercise, nutritional, and psychological interventions in patients with abdominal cancer receiving concurrent chemoradiotherapy: Prospective, multicenter, randomized trial.
Authors: Lei Yang, Wang Wen-bo, Yudi Xiong, Dedong Cao, Jing Dai, Hui Xu, Han Wu, Jin Peng, You Wang, Jing Su, Xin Chen, Qing-Yun Wang, Huangang Jiang, Ling Xia, Weidong Chen, Ximing Xu, Fuxiang Zhou
Journal: Journal of Clinical Oncology (2023)

e24138 Background: Concurrent chemoradiotherapy (CCRT) has several adverse toxicities such as fatigue, bone marrow suppression and malnutrition. We aimed to examine whether the mobile-based multimodal rehabilitation including exercise, nutritional and psychological interventions have an impact on clinical outcomes in abdominal cancer patients receiving concurrent chemoradiotherapy. Methods: A total of 90 eligible abdominal cancer patients were randomly assigned (1:1) to either the study (n = 47) or control (n = 43) group from February 2022 to November 2022. Multimodal rehabilitation was provided by a team of oncologists, rehabilitation physicians, nurses, clinical nutritionists and psychologists, while patients in the control group received only standard oncologic care. The study group received a wearable device and mobile app that provided an exercise program (at least 90 to 150 minutes of aerobic and resistance exercise per week for 5 weeks, depending on the patient's health status). Primary endpoints were changes in grip strength and body weight, with secondary endpoints including nutrition-related haematological indicators, toxicity and treatment completion rate. Results: Our study found that the body weight and grip strength of patients in the control group decreased significantly after CCRT, while those in the study group remained stable. The average weight loss (-0.19 ± 1.51 kg vs 1.28±1.90 kg, P = 0.016) and average grip strength loss (-0.95 ± 2.24 vs 1.26 ± 2.38 kg, P = 0.008) in the study group and control group after CCRT were significantly different. Meanwhile, patients in the study group showed less decline in haemoglobin levels (-1.96 ± 10.24 vs 12.05 ± 8.45 g/L, P = 0.000), serum albumin levels (0.65 ± 4.40 g/L vs 3.42 ± 2.87 g/L, P = 0.030) and lymphocyte count (0.74 ± 0.30 vs 1.16 ± 0.62 g/L, P = 0.010) contrast with control group. Conclusions: Multimodal rehabilitation based on mobile health could effectively maintain the body weight and nutritional status of patients undergoing concurrent chemoradiotherapy, which may be beneficial to improve the treatment tolerance of patients. Keywords: Abdominal cancer; Concurrent chemoradiotherapy; Multimodal rehabilitation; Mobile health; Grip strength. Clinical trial information: NCT05325554 .
Association between cervical immune markers and cervical high-risk HPV infections.
Authors: Sally Nneoma Adebamowo, Oluranti Ayotunde Famooto, Clement Adebayo Adebamowo
Journal: Journal of Clinical Oncology (2023)

e17522 Background: Evidence suggests that human papillomavirus (HPV) infection of the cervix, alters local immune markers. The aim of this study was to comprehensively evaluate the types and concentration of cervical cytokines and chemokines in HPV-negative compared to HPV-positive women in sub-Saharan African. Methods: The study population was 275 women enrolled in the African Collaborative Center for Microbiome and Genomics (ACCME) HPV cohort study. The concentration of 27 chemokines, cytokines and growth factors was quantified from cervical samples, using multiplexed bead-based immunoassays. HPV types were characterized using SPF 25 /LiPA 10 . Regression models were used to estimate the association between each immune marker and HPV infection. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for fold-change in immune marker levels divided into quartiles, using the lowest quantile as a reference category. Results: The mean (±SD) age of the women was 41 (±8) years. Some, 49% (134/275) were HPV negative and 51% (141/275) were HPV positive. Of the HPV positive women, 39% (55/141) had low-risk HPV (lrHPV) types and 93% (131/141) had high-risk HPV (hrHPV) types. Compared to HPV negative women, lrHPV-positive women had significantly higher median concentration of IFN-g, IL-2, IL-4, IL-7, IL-10 and IL-13. While hrHPV-positive women had significantly lower median concentration of GMCSF, interleukin (IL)-1RA and MCP-1; and higher median concentration of interferon-g (IFN-g), IL-b, IL-6, IL-7, IL-8, IL-9, IL-10, IL-13, IL-15 and MCP-1b, compared to HPV negative women. Women had significantly higher odds of lrHPV infection if they were in the highest quartile for IL-2, IL-4, IL-5, IL-7, IL-10, IL-12p70 and IL-13. While women had significantly lower odds of hrHPV infection if they were in the highest quartile for IL-IRA (OR 0.16, 95% CI: 0.07, 0.34) or MCP-1 (OR 0.39, 95% CI: 0.18, 0.83), and significantly higher odds of hrHPV infections if they were in the highest quartile for eotaxin, IFN-g, IL-1b, IL-4, IL-5, IL-7, IL-8, IL-9, IL-10, IL-13, IL-15, MIP-1a, MIP-1b or TNFa. Conclusions: Consistent with findings from other populations, higher concentration of pro-inflammatory immune markers in the cervix were associated with higher odds of high-risk HPV infections among African women.
Real-world treatment patterns and total cost of care in Medicare patients with metastatic pancreatic ductal adenocarcinoma who received first-line FOLFIRINOX.
Authors: Jared Hirsch, Paul Cockrum, Samantha Tomicki, Gabriela Dieguez, Prachi Bhatt, George P. Kim
Journal: Journal of Clinical Oncology (2023)

e16283 Background: Modifications to the FOLFIRINOX (FFX) regimen are used in the real world to attempt to decrease side effects and increase tolerability for patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). This study assesses patterns in real-world modifications to first-line (1L) FFX and total cost of care per administration cycle in the Medicare Fee-For-Service (FFS) population. Methods: We used ICD-10 diagnosis codes to identify patients aged 65+ with mPDAC without end-stage renal disease in the 2018-2021 Medicare Parts A, B, and D 100% Research Identifiable Files (RIF) data. Study patients had 2+ claims with a pancreatic cancer diagnosis and at least one diagnosis of a metastasis anytime on or after the first pancreatic cancer diagnosis. Total cost of care (TCOC) represents mean Medicare paid amounts and patient cost sharing. Lines of therapy (LOTs) were assigned based on therapies used. LOTs ended the day before a new chemotherapy began, 28 days after the last chemotherapy (if no new chemotherapy), or upon death. Study patients were assigned to cohorts based on drugs present within a 48-hour (2-day) period of a 1L FFX chemo infusion cycle: FFX with all 4 component drugs (oxaliplatin, irinotecan, leucovorin, 5-Fluorouracil (5-FU) bolus and infusion), FFX with no 5-FU bolus but with 5-FU infusion, FFX with a 5-FU bolus but no 5-FU infusion, FFX with no 5-FU of any kind, and FFX with no leucovorin. Results: We found 45,755 administrations of 1L FFX regimens across 8,889 patients with mPDAC between 2018 and 2021. Among 1L FFX regimens, the largest cohort was comprised of administrations involving a 5-FU infusion but no 5-FU bolus (21,619 administrations, or 47%). The second largest cohort received all 4 FFX component drugs (15,565 administrations, or 34%). The other cohorts were patients receiving FFX with no leucovorin (6,300 administrations, or 14%), FFX with a 5-FU bolus but no infusion (1,425 administrations, or 3%) and patients receiving FFX with no 5-FU of any kind (842 administrations, or 2%). Administrations containing all 4 drug components had the highest cost per cycle ($7,515), and those with no 5-FU of any kind had the lowest ($6,715). Conclusions: Among Medicare beneficiaries receiving 1L FOLFIRINOX (FFX) regimens to treat mPDAC, only 34% of administrations of FFX contained all four components. Administrations most frequently omitted the 5-FU bolus. Administrations containing all 4 drug components had higher costs per cycle and those with no 5-FU of any kind had the lowest cost per cycle.